20-pyridyl-5, 16-pregnadien-3, 20-diols and lower alkyl derivatives thereof



United States Patent 20-PYRIDYL-5,16-PREGNADlEN-3,20-DIOLS AND LOWERIALKYL DERIVATIVES THEREOF Raymond M. Dodson, ParkRidge, and Clarence G.Bergstrom,.Chicago, lll.,, assignors, by mesne assignments, to G. D.Searle & Co., Skokie, 111., a corporation of Delaware No Drawing,Application November 24, 1954, Serial No. 471,119

6 Claims. (Cl. 260-2395) The present invention relates to a new group ofpyridyl derivatives of pregnadiendiols and, more particularly, to20-pyridyl-5,l6-pregnadien-3,20diols and lower alkyl derivatives thereofwhich can be represented by the general structural formula wherein R andR represent hydrogen or lower alkyl radicals, such as methyl, ethyl,propyl, butyl and the like.

These compounds can be synthesized by treatment of3-hydroxy-5,16-pregnadien-20-one or a readily hydrolyzable ester thereofsuch as a lower alkanoyl or benzoyl ester with an organometallicpyridinesderivative such as pyridyl lithium, pyridyl sodium,methylpyridyl lithium, dimethylpyridyl lithium, ethylpyridyl sodium andthe like.

The bases described herein form salts which are nontoxic in therapeuticdosage with a variety of inorganic and strong organic acids such asphosphoric, hydrochloric, hydrobromic, hydriodic, .sulfamic, acetic,maleic, malic, succinic, tartaric, citric, ascorbic, gluconic, benzoic,cinnamic, and related acids.

The-compounds of this invention are valuable intermediates in thesynthesis of medicinally active compounds. They are especially valuableas starting materials for the preparation of solanidinoidal alkaloids.Thus, a compound of the type 2,750,380 atented,- June 12-; .956.

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2 by boiling in diluteethanol to yield a dehydrosolanidinoid containingan aromatic ring-F of the formula which can then be hydrogenated usingsodium or lithium in ethanol or ammonia to form a compound of the typeEsterification of the latter with a lower alkanoyl halide or anhydride.followed by quaternization with methyl sulfate yields a solanidiniumtype of quaternary salt of the cationic formula which has a veratrinetype of action on the heart muscle. The compounds of this invention canalso be oxidized by Qpenauer oxidation to form the corresponding 4,16-

pregnadienJ-ones of the type ,Conventional treatmentof the 3,2 0-diolsof this invention with an equivalent of an alkanoyl or aroyl halideor'an alkanoic acid anhydride yields the 3-monoesters.

A special utility of the compounds of this invention is their stimulantaction on the hypodynamic or failing heart manifested by a restorationof the deficient contractility of the heart muscle and of the deficientcardiac output. This effect is quite different from the jervinelikedepressant cardiac action shown by the corresponding 16,17-dihydroderivatives.

The following examples will illustrate in further detail some of thecompounds which constitute this invention and methods for theirpreparation. However, this invention is not to be construed as limitedthereby in spirit or in scope, since modifications in materials andoperating conditions can be adopted without departing from theinvention. In these examples temperatures are indicated in degreescentigrade and quantities of materials in parts by weight.

Example 1 A solution of butyl lithium in 70 parts of ether is preparedfrom 1.87 parts of lithium and 16 parts of 1bromobutane. This solutionis cooled to 40 C. and stirred while 17.7 parts of a-bromopyridine areadded dropwise in the course of minutes. While stirring is continued asolution of 10 parts of 3,3-acetoxy-5,16-preguadien-20- one in 350 partsof anhydrous ether is added rapidly. The cooling bath is removed and thesolution is stirred for 2 hours at room temperature. After standing atroom temperature for hours, the solution is treated with 250 parts ofwater. The ether layer is separated, washed with water to neutrality,dried over anhydrous sodium sulfate, filtered and evaporated to dryness.The residue is applied in benzene solution to a chromatography columncontaining 900 parts of silica gel. the column with 7000 parts of a 4%and 7000 parts of an 8% solution of ethyl acetate in benzene removessome impurities. Further elution with 22,500 parts of an 8% solution ofethyl acetate in benzene causes elution of one of the epimeric isomersof -(a-pyridyl) -5,16- pregnadien-3B,20-diol. A second epimer is elutedwith 12,000 parts of a 20% solution of ethyl acetate in benzene.Repeated crystallization from acetone of the first epimer produces apure product melting at about 186 187 C. The optical rotation of an0.705% chloroform solution is [a] =66. Ultraviolet maxima are observedat 255.5 and 261 millimicrons with molecular extinction coefiicients of3820 and 4310, respectively. The infrared spectrum shows prominent bandsat 2.93, 3.10, 6.30, 7.00, 7.28, 9.38, 10.38, and 13.24 microns.

Repeated crystallization from acetone of the epimer second to be lutedyields a product melting at about 180-182 C. The specific rotation of a1.1% chloroform solution is -31.6. Ultraviolet maxima are observed at257 and 261 millimicrons with molecular extinction coefficients of 3940and 4310, respectively. The infrared spectrum shows prominent bands at2.94, 3.04, 6.29, 6.99, 7.32, 9.43, 9.56, 10.34, and 13.25 microns.

The same reaction can also be carried out with the 3a-epimer of3-acetoxy-5,l6-pregnadien-20-one. The unacetylated3-hydroxy-5,l6-pregnadien-20-one can likewise be used.

Example 2 A solution of 95 parts of20-(a-pyridyl)-5,16-pregnadien-3,B,20-diol, melting at about 186-187 C.,is added to a mixture of 1000 parts of pyridine and 1100 parts of aceticanhydride. After standing at room temperature for 12 hours, the mixtureis treated with water to cause precipitation of a 39-acetoxy-20-(a-pyridyl)-5,16- pregnadien-20-ol which onrecrystallization from acetone melts at about 167-168 C. The rotation ofan 0.3% chloroform solution is [a] =49.5. The ultraviolet absorptionspectrum shows a maximum at 256 millimicrons with a molecular extinctioncoefiicient of 3800,

Elution of 7 4 v a maximum at 261 millimicrons with a molecularextinction coeflicient of 4300, and a shoulder at about 270 millimicronswith a molecular extinction coeflicient of 2150. The infrared spectrumshows maxima at 2.84, 5.76, 6.31, 6.98, 7.24, 7.34, 7.98, 9.64, 12.75,and 13.17 microns, respectively.

Example 3 A solution of 97 parts of the epimer of 20-(a-pyridyl)-5,l6-pregnadien-3B,20-diol melting at about 180-182 C. in 1000 parts ofpyridine and 1050 parts of acetic anhydride is maintained at roomtemperature for 12 hours and then treated with Water. The resulting precipitate is collected on a filter and crystallized from acetone to yielda 3,8-acetoxy-20-(a-pyridyl)-5,16-pregnadien-20-ol melting at about174-176 C. The specific rotation of an 0.64% chloroform solution is u=26.6. The ultraviolet spectrum shows two maxima at 256 and 261.5millimicrons and a shoulder at 270 millimicrons; the molecularextinction coefiicients are 4170, 4600, and 2790, respectively. Infraredmaxima are observed at about 2.94, 5.75, 6.29, 6.97, 8.00, and 9.63microns.

Example 4 Substitution of an equal amount of 3-bromopyridine for the2-bromopyridine used in Example 1 leads to formation of a mixture of twoisomers of 20-(fl-pyridyl)- 5,16-pregnadien-3,20-diol epimeric at carbon20. The ultraviolet absorption spectrum shows maxima at 25 7 and 263millimicrons with molecular extinction coefiicients of about 3900 and4300, respectively. Infrared maxima are observed at about 2.90, 3.06,6.30, and 6.98 microns.

Example 5 A solution of butyl lithium in parts of ether, prepared from3.74 parts of lithium and 32 parts of l-bromobutane is cooled to 40 C.and then treated by dropwise addition with 35.4 parts of 4-bromopyridinein the course of 10 minutes. Stirring is continued while 20 parts ofB-hydroxy-S,16-pregnadien-20-one in 1000 parts of ether are added. Themixture is then stirred at 25 C. for 6 hours, after which 500 parts ofwater are added. The ether layer is Washed with water to neutrality,filtered and concentrated to dryness. The resulting product isrepeatedly recrystallized from acetone to yield20(y-pyridyl)-5,16-pregnadien-3,20-diol. Two isomers epimeric atcarbon-20 can be separated by chromatography on silica gel by the methodof Example 1. The compound shows an ultraviolet maximum at about 251millimicrons with a molecular extinction coefficient of about 4300.Infrared maxima are observed at 2.94, 3.08, 6.3, and 7.0 microns.

Example 6 Substitution of 41.6 parts of 2-bromo-4,6-dimethyl pyridinefor the 4-bromopyridine used in the preceding example, yields20-(4',6'-dimethyl-2'-pyridyl)-5,16-pregnadien-3,20-diol. The compoundshows an ultraviolet plateau at about 260-270 millimicrons with anextinction coefficient of about 4000. It has the structural formula CH3CH3 5 What is claimed is: 1. A compound of the structural formula 6wherein R and R' are members of the class consisting of hydrogen andlower alkyl radicals.

2. 20-pyridyl-5,l6-pregnadien-3,20-diol. 3. 20- u-pyridyl -5 16-pregnadien-3,20-diol. 5 4. 20-(fi-pyridyl) -5,l6-pregnadien3,20-diol.5. 20- ('y-pyridyl) -5, 1 6-pregnadien-3,20-diol. 6 20 [(loweralkyl)pyridyl]5,16-pregnadien 3,20-

10 References Cited in the file of this patent I UNITED STATES PATENTS2,665,274 Conbere Jan. 5, 1954

1. A COMPOUND OF THE STRUCTURAL FORMULA